Research PaperMorphine produces potent antinociception, sedation, and hypothermia in humanized mice expressing human mu-opioid receptor splice variantsHuang, Yi-Hana,b; Wu, Yu-Weic; Chuang, Jian-Yinga; Chang, Yung-Chiaob; Chang, Hsiao-Fub; Tao, Pao-Luhd; Loh, Horace H.e,f; Yeh, Shiu-Hwaa,b,*Author Information aPh.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan bInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan cGraduate Institute of Biomedical Informatics, College of Medicine Science and Technology, Taipei Medical University, Taipei, Taiwan dCenter for Neuropsychiatric Research, National Heath Research Institutes, Miaoli, Taiwan eDepartment of Pharmacology, Medical School University of Minnesota, Minneapolis, MN, United States fGeneral Pain Institute, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, China *Corresponding author. Address: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan. Tel.: (886)-37-246166 ext. 35759; fax: (886)-37-586456. E-mail address: firstname.lastname@example.org (S.-H. Yeh). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com). PAIN: June 2020 - Volume 161 - Issue 6 - p 1177-1190 doi: 10.1097/j.pain.0000000000001823 Buy SDC Metrics AbstractIn Brief Morphine is a strong painkiller acting through mu-opioid receptor (MOR). Full-length 7-transmembrane (TM) variants of MOR share similar amino acid sequences of TM domains in rodents and humans; however, interspecies differences in N- and C-terminal amino acid sequences of MOR splice variants dramatically affect the downstream signaling. Thus, it is essential to develop a mouse model that expresses human MOR splice variants for opioid pharmacological studies. We generated 2 lines of fully humanized MOR mice (hMOR+; mMOR−/− mice), line #1 and #2. The novel murine model having human OPRM1 genes and human-specific variants was examined by reverse-transcription polymerase chain reaction and the MinION nanopore sequencing. The differences in the regional distribution of MOR between wild-type and humanized MOR mice brains were detected by RNAscope and radioligand binding assay. hMOR+; mMOR−/− mice were characterized in vivo using a tail-flick, charcoal meal, open field, tail suspension, naloxone precipitation tests, and rectal temperature measurement. The data indicated that wild-type and humanized MOR mice exhibited different pharmacology of morphine, including antinociception, tolerance, sedation, and withdrawal syndromes, suggesting the presence of species difference between mouse and human MORs. Therefore, hMOR+; mMOR−/− mice could serve as a novel mouse model for pharmacogenetic studies of opioids. Morphine induces potent antinociception and severe constipation, sedation, and hypothermia; however, it exhibits minor antinociceptive tolerance in fully humanized mu-opioid receptor mouse model. © 2020 International Association for the Study of Pain.